Polymer-supported catalysts are widely used in chemical processes. Much of the technology that is presently available derives from the solid-phase peptide synthesis techniques developed by Merrifield. These techniques are based on insoluble cross-linked polystyrene supports. Catalysts supported on Merrifield resins can be recovered from reaction media using a solid/liquid separation technique such as filtration.
With the growing interest in environmentally friendly, or “green” chemical processes, there is an emphasis on the ability to reuse materials and to minimize amounts of solvents required for a given process. Filtration is typically a relative solvent-intensive process, because the recovered solid is typically rinsed with additional solvent. Further, some polymer-supported catalysts suffer from decreased activity once they are isolated via filtration. This impacts their potential to be reused multiple times.
Soluble polymer-supported catalysts have been developed. These catalysts can be recovered from the reaction medium either by precipitation followed by filtration, by liquid/liquid separation, or by ultrafiltration using a filtration membrane. Precipitation/filtration obviously suffers from the same drawbacks associated with the filtration of insoluble polymer-supported catalysts, described above. Inadequate partitioning of the catalyst into the desired liquid phase often impairs liquid/liquid separations. For example, liquid/liquid separation is impractical if the catalyst and the product are both soluble in the same phase. Ultrafiltration of soluble catalysts using membranes has enjoyed some success, but the recycled catalysts often suffer from some loss of activity.
An alternative way of using a soluble catalyst is to use a biphasic system wherein the catalyst is preferentially soluble in one phase and the substrate and/or products are soluble in the other phase. To allow the reaction to proceed using this setup, the biphasic solvent system is vigorously mixed to ensure maximum contact between the catalyst and substrate. After the reaction, the mixture is allowed to settle and the product phase is removed, leaving the catalyst phase available for more reactions. This constitutes an example by which the soluble catalyst is recycled. The drawback to biphasic systems is that the presence of multiple phases introduces kinetic barriers to reaction. Such barriers result for the lack of solubility of both the catalyst and substrate in the same reaction solvent, which lowers the interaction rate between these reaction components.
The drawbacks associated with biphasic solvent systems can be overcome by using a solvent system that is monophasic under one set of conditions and biphasic under a different set of conditions. For example, liquid-liquid biphasic systems that exhibit an increase in phase miscibility at an elevated temperature and incorporate soluble polymer-bound catalysts having a strong phase preference at ambient temperature have been described by Bergbreiter and colleagues (2000, 2001; both references of which are herein incorporated by reference in their entirety).
Such thermomorphic biphasic reaction systems are also referred to as latent biphasic reaction systems, which are described in U.S. Pat. No. 7,211,705 (incorporated herein by reference in its entirety). This publication describes other latent biphasic reactions where conditions such as ion concentration are modified to effect the switch from the biphasic state (i.e. two or more solvents are immiscible) to the monophasic state in which the solvents become miscible with one another, creating a heterogeneous solvent. Upon reaction completion, the biphasic state (or multiphasic state) must be restored in order to regain access to catalyst apart from the product. Consequently, latent biphasic solvent systems can be rather complex, necessitating the empirical determination of conditions that will effectively govern a reversible phase transition allowing i) effective mixing of catalyst with substrate, and ii) separation of catalyst from product.
A process that is similar to the above-described latent biphasic systems has previously been described (Bergbreiter et al., 2003). In that process, substrate and soluble catalyst are initially dissolved in a homogeneous solvent containing at least two different solvents. The conditions are such that only a slight modification, or perturbation, of the reaction system will result in the immiscibility and separation of the different solvents (i.e. the system is partly latently biphasic). The strategy in this case is to ensure that the catalyst and reaction product are not greatly soluble in the same solvent after system perturbation. Shared solubility obviously impedes acquisition of pure catalyst.
In view of the prior art, there remains a need for catalytic methods that allow for the efficient separation of the catalyst from the reaction product and the recycling of the catalyst. Further, there is a need for such methods wherein the recycled catalyst is highly reusable. It is desirable that such methods operate with minimal additional solvent to effect the separation of the catalyst.